The Immune Mechanisms and Pathogenesis Working Group (WG1) has capitalized on major institutional strengths in immunology and host defense to develop a highly interactive and successful network of 40 CFAR investigators, including researchers with basic and translational backgrounds. Collectively they have published 526 peer-reviewed publications during the last funding cycle on the immunological determinants of HIV disease pathogenesis. Seminal studies performed by WG1 investigators have led the HIV research field into recognition of the importance of immune activation and inflammation in HIV pathogenesis. Specifically the group has shown that indices of inflammation and coagulation are key predictors (not just concomitants) of the clinical complications of treated HIV infection. The key scientific objectives for the next few years are to rigorously define the immunopathogenic drivers and pursue studies in the following three key opportunity areas: (i) Molecular mechanisms for enhanced systemic inflammation and clinical complications in HIV disease (ii) Immune failure and immune restoration (iii) Innate mucosal defenses against HIV Thus the overall scientific goal of this Working Group is to provide a new understanding of disease progression in the ART era and to develop and test interventional strategies that will improve outcomes for patients. The group achieves these objectives by initiating and sustaining collaborative projects among its members. The Specific Aims of WG1 are: ? To develop new interactions among investigators from various disciplines ? To stimulate the formation of multi-investigator projects ? To stimulate cross-fertilization between working groups The research pursued by WG1 investigators is linked intimately with the goals of the Virology and Cure WG2 and the HIV and Co-Infections and Co-Morbidities WG3 and there is frequent cross-fertilization between the groups.